Abstract Body

The apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer disease (AD). In addition to effects of ApoE on amyloid-β, results have shown that ApoE markedly influences pathological forms of tau and tau-mediated neurodegeneration with apoE4 having a strong deleterious effect on both parameters. In the brain, ApoE is produced and secreted primarily by astrocytes and also by activated microglia though the cell-specific role of each form of ApoE in the setting of neurodegeneration has not been determined. We utilized a well characterized mouse model of tauopathy, P301S Tau transgenic mice expressing floxed APOE-ε4 or APOE-ε3 alleles. We crossed these mice with Aldh1l1-CreERT2 mice and at 5.5 months of age, after the onset of tau pathology, administered tamoxifen or vehicle. We then compared mice with or without inducible knockout of astrocyte APOE at 9 months of age. Removing astrocytic APOE4 but not APOE3 markedly reduced tau-mediated neurodegeneration, decreased p-tau pathology, and improved nesting behavior. Single nucleus RNA sequencing analysis revealed striking gene expression changes in all cell types in P301S mice with astrocytic APOE4 playing a role in modulating neuron and astrocyte gene expression with little effect on microglial gene expression. Importantly, removal of astrocytic APOE4 decreased tau-induced synaptic loss and microglial phagocytosis of synaptic elements suggesting a key role for astrocytic APOE in synaptic degeneration.